Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Biomedical Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 2049-9434 Online ISSN: 2049-9442
Journal Cover
November-2026 Volume 25 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
November-2026 Volume 25 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML

  • Supplementary Files
    • Supplementary_Data1.pdf
    • Supplementary_Data2.pdf
Article Open Access

Nrf2 and PGC‑1α signaling in temozolomide resistance in glioblastoma under hypoxia

  • Authors:
    • Pinpat Tripatara
    • Tasanee Onkoksoong
    • Sunisa Prasopporn
    • Sith Sathornsumetee
    • Siwanon Jirawatnotai
    • Uraiwan Panich
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
    Copyright: © Tripatara et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 129
    |
    Published online on: September 11, 2026
       https://doi.org/10.3892/br.2026.2202
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:


Abstract

Hypoxia is a key contributor to chemoresistance in glioblastoma (GBM), partly through the activation of nuclear factor erythroid 2‑related factor 2 (Nrf2)‑dependent cellular stress responses and mitochondrial adaptive programs. The present study investigated Nrf2 signaling in hypoxia-associated resistance to temozolomide (TMZ) in U87MG cells, a glioblastoma cell line, and evaluated whether pharmacological suppression of Nrf2 pathway output with brusatol enhances TMZ sensitivity under hypoxic conditions. U87MG cells were cultured under normoxic or hypoxic conditions (1% O2) and treated with TMZ, brusatol, or their combination. DAPI‑based cell‑counting assays were used to determine half‑maximal inhibitory concentrations (IC50 values) and assess drug interactions by combination index analysis. Hypoxia‑inducible factor 1α (HIF‑1α) expression, epidermal growth factor receptor (EGFR) phosphorylation and Nrf2 nuclear accumulation were analyzed by western blotting. The expression of antioxidant and growth factor‑related signaling genes and downstream targets of peroxisome proliferator‑activated receptor gamma coactivator 1α (PGC‑1α), a key regulator of mitochondrial bioenergetics, was quantified by real‑time PCR (qPCR). PGC‑1α subcellular localization and oxidative DNA damage, assessed using 8‑hydroxy‑2'‑deoxyguanosine, were evaluated by immunofluorescence. Hypoxia markedly increased the TMZ IC50 and was accompanied by elevated HIF‑1α expression and enhanced Nrf2 nuclear accumulation. Combination index analysis identified synergistic interactions between TMZ and brusatol under normoxia, whereas no synergistic interaction was detected under hypoxia; nonetheless, brusatol still enhanced TMZ sensitivity under hypoxia based on direct cell-count analysis. Hypoxia markedly upregulated antioxidant genes (GCLM, GPX1, GSTP1, HO‑1, NQO1 and SOD1) and growth‑ and survival‑related genes (NF‑κB, TGF‑β, EGF and EGFR) and induced a PGC‑1α‑associated mitochondrial transcriptional program, as evidenced by increased expression of sirtuin 3, cytochrome c and ATP synthase F1 subunit β. Co‑treatment with TMZ and brusatol suppressed antioxidant gene expression, reduced EGFR phosphorylation, attenuated PGC‑1α‑linked mitochondrial gene expression, and increased oxidative DNA damage. These findings indicated that pharmacological suppression of Nrf2 pathway output by brusatol was associated with enhanced TMZ sensitivity under hypoxic conditions in U87MG cells, together with reduced antioxidant gene expression, lower EGFR phosphorylation, attenuation of PGC‑1α‑associated mitochondrial responses, and increased oxidative DNA damage in GBM, potentially reflecting suppression of HIF‑1α‑dependent as well as Nrf2‑dependent signaling.
View Figures

Figure 1

Effects of TMZ and Bru on relative
cell number in U87MG and U138MG cells under normoxia and hypoxia.
(A) U87MG cell proliferation under normoxia (21% O2) or
hypoxia (1% O2) for up to 72 h. Dose-response curves for
(B) TMZ (3-300 µM) and (C) Bru (7.5-120 nM). (D) U138MG cell
proliferation under normoxia or hypoxia for up to 72 h.
Dose-response curves for (E) TMZ and (F) Bru after 72 h under
normoxia or hypoxia, assessed by DAPI-based cell counting. Data are
presented as the mean ± SD (n≥3). Differences between normoxia and
hypoxia at each time point or matched concentration were evaluated
using unpaired two-tailed Student's t-test. *P<0.05,
**P<0.01, and ***P<0.001 vs. normoxia.
TMZ, temozolomide; Bru, brusatol.

Figure 2

Hypoxia induces HIF-1α and activates
Nrf2 signaling in U87MG cells. U87MG cells were exposed to hypoxia
(1% O2) for the indicated durations. (A) Representative
immunoblots and quantification of HIF-1α. Nrf2 nuclear accumulation
was assessed by fractionation followed by immunoblotting: (B)
representative blots and quantification of (C) the N/C Nrf2 ratio,
(D) nuclear Nrf2, (E) cytosolic Nrf2 and (F) total Nrf2. For Nrf2
immunoblots, quantification was restricted to the band in the
expected molecular-weight region (100-130 kDa);
lower-molecular-weight nonspecific bands were not quantified. (G)
Nrf2 mRNA expression measured by qPCR. (H) Intracellular ROS
measured by DCFH-DA staining and flow cytometry and (I) the
corresponding quantification expressed as a percentage of the
normoxic control. Data are presented as the mean ± SD (n≥3).
Statistical significance was determined by one-way ANOVA followed
by Dunnett's post hoc test. *P<0.05,
**P<0.01 and ***P<0.001 vs. normoxia.
HIF-1α, hypoxia-inducible factor 1 alpha; Nrf2, nuclear factor
erythroid 2-related factor 2; N/C, nuclear/cytosolic; qPCR,
quantitative polymerase chain reaction; ROS, reactive oxygen
species; DCFH-DA, 2',7'-dichlorodihydrofluorescein diacetate;
ctr-norm, normoxic control.

Figure 3

Bru enhances TMZ sensitivity in U87MG
cells under conditions associated with suppression of Nrf2 pathway
output. U87MG cells were treated with TMZ (0-300 µM) with or
without Bru (30 nM) for 72 h under normoxia or hypoxia, and
relative cell number was assessed by DAPI-based cell counting.
Dose-response curves were generated under (A) normoxia and (B)
hypoxia. Values are expressed as percentages of the corresponding 0
µM TMZ condition within each curve; thus, each TMZ dose-response
curve was normalized to its own baseline (100%). At matched TMZ
concentrations, TMZ alone and TMZ plus Bru were compared using
unpaired two-tailed Student's t-test. *P<0.05,
**P<0.01, and ***P<0.001 vs. TMZ at the
same concentration without Bru. Heat maps show the CI for
TMZ-brusatol combinations under (C) normoxia and (D) hypoxia.
CI<1, CI=1 and CI>1 indicate synergism, additivity and
antagonism, respectively. Bru, brusatol; TMZ, temozolomide; Nrf2,
nuclear factor erythroid 2-related factor 2; CI, combination
index.

Figure 4

Hypoxia induces antioxidant and
growth factor-related gene expression and activates EGFR signaling
in U87MG cells. U87MG cells were exposed to normoxia or hypoxia (1%
O2) and treated with TMZ and/or Bru as indicated. (A)
mRNA expression of antioxidant and growth factor-related signaling
genes under normoxia and hypoxia, measured by qPCR. (B) Heat map of
gene-expression changes in hypoxic cells treated with TMZ and/or
Bru. (C) Representative immunoblots and quantification of the
p-EGFR/EGFR ratio under normoxia and hypoxia. (D) Representative
immunoblots and quantification of the p-EGFR/EGFR ratio in hypoxic
cells treated with TMZ and/or Bru. Data are presented as the mean ±
SD (n≥3). Comparisons between normoxic and hypoxic controls and
between TMZ-alone and combination treatment groups were performed
using an unpaired two-tailed Student's t-test
(***P<0.001, ###P<0.001, and
$P<0.05, as indicated). Comparisons among multiple
treatment groups were analyzed using one-way ANOVA followed by
Dunnett's post hoc test (*P<0.05 vs. the hypoxic
control). EGFR, epidermal growth factor receptor; TMZ,
temozolomide; Bru, brusatol; qPCR, quantitative polymerase chain
reaction; p-, phosphorylated.

Figure 5

Bru-associated TMZ sensitization is
accompanied by attenuation of the hypoxia-induced PGC-1α axis and
increased oxidative DNA damage in U87MG cells. U87MG cells were
treated with TMZ and/or Bru under hypoxia (1% O2) for 24
h. Immunofluorescence analysis of PGC-1α expression and nuclear
localization. (A) Representative images of PGC-1α (Alexa Fluor 647)
and nuclei (DAPI). Quantification includes (B) the
nuclear-to-cytoplasmic fluorescence intensity ratio and (C)
nuclear, (D) cytoplasmic and (E) whole-cell mean PGC-1α
fluorescence intensities. Expression of (F) PGC-1α and the
downstream mitochondrial genes (G) SIRT3, (H) CYCS and (I) ATP5F1B,
measured by qPCR. Oxidative DNA damage assessed by 8-OHdG staining:
(J) Representative images (magnification, x40) and (K)
quantification of whole-cell mean 8-OHdG intensity. Data are
presented as the mean ± SD (n≥3). Comparisons between normoxic and
hypoxic controls and between TMZ-alone and combination treatment
groups were performed using an unpaired two-tailed Student's t-test
(##P<0.01 ###P<0.001 and
$P<0.05, $$P<0.01,
$$$P<0.001 respectively). Comparisons among multiple
treatment groups were analyzed using one-way ANOVA followed by
Dunnett's post hoc test (*P<0.05,
**P<0.01, and ***P<0.001 vs. the
hypoxic control). Bru, brusatol; TMZ, temozolomide; PGC-1α,
peroxisome proliferator-activated receptor gamma coactivator 1
alpha; 8-OHdG, 8-hydroxy-2'-deoxyguanosine; SIRT3, sirtuin 3; CYCS,
cytochrome c; ATP5F1B, ATP synthase F1 subunit β; qPCR,
quantitative polymerase chain reaction; ctr-norm, normoxic control;
ctr-hyp, hypoxic control.

Figure 6

Proposed model of hypoxia-associated
Nrf2 and PGC-1α signaling in temozolomide resistance in
glioblastoma. Under hypoxia, U87MG glioblastoma cells show
increased nuclear accumulation of Nrf2 and HIF-1α, which engage ARE
and HRE, respectively. This drives upregulation of antioxidant and
cytoprotective genes, including GCLM, HO-1, NQO1, and SOD1, as well
as members of the GPX and GST gene families, together with growth-
and survival-related genes (NF-κB, EGF, TGF-β, and EGFR), and a
PGC-1α-associated mitochondrial transcriptional program (including
SIRT3 and ATP5F1B), while limiting oxidative DNA damage (8-OHdG),
collectively contributing to temozolomide resistance.
Pharmacological suppression of Nrf2 pathway output with brusatol
attenuates these hypoxia-adaptive responses, reducing antioxidant
and growth factor-related gene expression and PGC-1α-linked
mitochondrial responses while increasing oxidative DNA damage,
thereby enhancing temozolomide sensitivity under hypoxic
conditions. Nrf2, nuclear factor erythroid 2-related factor 2;
PGC-1α, peroxisome proliferator-activated receptor gamma
coactivator 1 alpha; HIF-1α, hypoxia-inducible factor 1 alpha; ARE,
antioxidant response elements; HRE, hypoxia response elements;
GCLM, glutamate-cysteine ligase modifier subunit; HO-1, heme
oxygenase 1; GPX, glutathione peroxidase; NQO1, NAD(P)H quinone
oxidoreductase 1; GST, glutathione S-transferase; SOD1, superoxide
dismutase 1; NF-κB, nuclear factor kappa B; EGF, epidermal growth
factor; TGF-β, transforming growth factor beta; EGFR, epidermal
growth factor receptor; SIRT3, sirtuin 3; ATP5F1B, ATP synthase F1
subunit beta; 8-OHdG, 8-hydroxy-2'-deoxyguanosine; ROS, reactive
oxygen species.
View References

1 

Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS and Khasraw M: Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 70:299–312. 2020.PubMed/NCBI View Article : Google Scholar

2 

Sousa N, Geiß C, Bindila L, Lieberwirth I, Kim E and Régnier-Vigouroux A: Targeting sphingolipid metabolism with the sphingosine kinase inhibitor SKI-II overcomes hypoxia-induced chemotherapy resistance in glioblastoma cells: Effects on cell death, self-renewal, and invasion. BMC Cancer. 23(762)2023.PubMed/NCBI View Article : Google Scholar

3 

Thakur A, Faujdar C, Sharma R, Sharma S, Malik B, Nepali K and Liou JP: Glioblastoma: Current status, emerging targets, and recent advances. J Med Chem. 65:8596–8685. 2022.PubMed/NCBI View Article : Google Scholar

4 

Monteiro AR, Hill R, Pilkington GJ and Madureira PA: The role of hypoxia in glioblastoma invasion. Cells. 6(45)2017.PubMed/NCBI View Article : Google Scholar

5 

Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L and Kolb HC: The clinical importance of assessing tumor hypoxia: Relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid Redox Signal. 21:1516–1554. 2014.PubMed/NCBI View Article : Google Scholar

6 

Ge X, Pan MH, Wang L, Li W, Jiang C, He J, Abouzid K, Liu LZ, Shi Z and Jiang BH: Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a/Bad/Bax axis. Cell Death Dis. 9(1128)2018.PubMed/NCBI View Article : Google Scholar

7 

Singh N, Miner A, Hennis L and Mittal S: Mechanisms of temozolomide resistance in glioblastoma-a comprehensive review. Cancer Drug Resist. 4:17–43. 2021.PubMed/NCBI View Article : Google Scholar

8 

Mao XG, Xue XY, Lv R, Ji A, Shi TY, Chen XY, Jiang XF and Zhang X: CEBPD is a master transcriptional factor for hypoxia regulated proteins in glioblastoma and augments hypoxia induced invasion through extracellular matrix-integrin mediated EGFR/PI3K pathway. Cell Death Dis. 14(269)2023.PubMed/NCBI View Article : Google Scholar

9 

Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM and Schumacker PT: Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing. J Biol Chem. 275:25130–25138. 2000.PubMed/NCBI View Article : Google Scholar

10 

Schroedl C, McClintock DS, Budinger GRS and Chandel NS: Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol. 283:L922–L931. 2002.PubMed/NCBI View Article : Google Scholar

11 

Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U and Schumacker PT: Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 1:401–408. 2005.PubMed/NCBI View Article : Google Scholar

12 

Masson N, Willam C, Maxwell PH, Pugh CW and Ratcliffe PJ: Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 20:5197–5206. 2001.PubMed/NCBI View Article : Google Scholar

13 

Chan DA, Sutphin PD, Yen SE and Giaccia AJ: Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 alpha. Mol Cell Biol. 25:6415–6426. 2005.PubMed/NCBI View Article : Google Scholar

14 

Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K and Yamamoto M: Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 24:7130–7139. 2004.PubMed/NCBI View Article : Google Scholar

15 

Bae T, Hallis SP and Kwak MK: Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer. Exp Mol Med. 56:501–514. 2024.PubMed/NCBI View Article : Google Scholar

16 

Ji X, Wang H, Zhu J, Zhu L, Pan H, Li W, Zhou Y, Cong Z, Yan F and Chen S: Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Int J Cancer. 135:574–584. 2014.PubMed/NCBI View Article : Google Scholar

17 

Tang T, Jia Y, Liang H, Han Y, Cong Z, Wang H and Ji X: Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia. Transl Cancer Res. 11:4105–4116. 2022.PubMed/NCBI View Article : Google Scholar

18 

Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, et al: Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 29:1235–1243. 2008.PubMed/NCBI View Article : Google Scholar

19 

Tan Z, Luo X, Xiao L, Tang M, Bode AM, Dong Z and Cao Y: The role of PGC1α in cancer metabolism and its therapeutic implications. Mol Cancer Ther. 15:774–782. 2016.PubMed/NCBI View Article : Google Scholar

20 

Luchkova A, Mata A and Cadenas S: Nrf2 as a regulator of energy metabolism and mitochondrial function. FEBS Lett. 598:2092–2105. 2024.PubMed/NCBI View Article : Google Scholar

21 

Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA and Zhang DD: Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci USA. 108:1433–1438. 2011.PubMed/NCBI View Article : Google Scholar

22 

Harder B, Tian W, La Clair JJ, Tan AC, Ooi A, Chapman E and Zhang DD: Brusatol overcomes chemoresistance through inhibition of protein translation. Mol Carcinog. 56:1493–1500. 2017.PubMed/NCBI View Article : Google Scholar

23 

Olayanju A, Copple IM, Bryan HK, Edge GT, Sison RL, Wong MW, Lai ZQ, Lin ZX, Dunn K, Sanderson CM, et al: Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2. Free Radic Biol Med. 78:202–212. 2015.PubMed/NCBI View Article : Google Scholar

24 

Shankar A, Jain M, Lim MJ, Angara K, Zeng P, Arbab SA, Iskander A, Ara R, Arbab AS and Achyut BR: Anti-VEGFR2 driven nuclear translocation of VEGFR2 and acquired malignant hallmarks are mutation dependent in glioblastoma. J Cancer Sci Ther. 8:172–178. 2016.PubMed/NCBI View Article : Google Scholar

25 

Suppramote O, Prasopporn S, Aroonpruksakul S, Ponvilawan B, Makjaroen J, Suntiparpluacha M, Korphaisarn K, Charngkaew K, Chanwat R, Pisitkun T, et al: The acquired vulnerability caused by CDK4/6 inhibition promotes drug synergism between oxaliplatin and palbociclib in cholangiocarcinoma. Front Oncol. 12(877194)2022.PubMed/NCBI View Article : Google Scholar

26 

Lohakul J, Chaiprasongsuk A, Jeayeng S, Saelim M, Muanjumpon P, Thanachaiphiwat S, Tripatara P, Soontrapa K, Lumlerdkij N, Akarasereenont P and Panich U: The protective effect of polyherbal formulation, harak formula, on UVA-induced photoaging of human dermal fibroblasts and mouse skin via promoting Nrf2-regulated antioxidant defense. Front Pharmacol. 12(649820)2021.PubMed/NCBI View Article : Google Scholar

27 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar

28 

Chaiprasongsuk A, Onkoksoong T, Pluemsamran T, Limsaengurai S and Panich U: Photoprotection by dietary phenolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responses. Redox Biol. 8:79–90. 2016.PubMed/NCBI View Article : Google Scholar

29 

Htut NW, Onkoksoong T, Saelim M, Kueanjinda P, Sampattavanich S and Panich U: Live-cell imaging Unveils stimulus-specific dynamics of Nrf2 activation in UV-exposed melanoma cells: Implications for antioxidant compound screening. Free Radic Biol Med. 211:1–11. 2024.PubMed/NCBI View Article : Google Scholar

30 

Arfin S, Jha NK, Jha SK, Kesari KK, Ruokolainen J, Roychoudhury S, Rathi B and Kumar D: Oxidative stress in cancer cell metabolism. Antioxidants (Basel). 10(642)2021.PubMed/NCBI View Article : Google Scholar

31 

Dai Z, Cai L, Chen Y, Wang S, Zhang Q, Wang C, Tu M, Zhu Z, Li Q and Lu X: Brusatol inhibits proliferation and invasion of glioblastoma by down-regulating the expression of ECM1. Front Pharmacol. 12(775680)2021.PubMed/NCBI View Article : Google Scholar

32 

Gao Y, Zhang E, Liu B, Zhou K, He S, Feng L, Wu G, Cao M, Wu H, Cui Y, et al: Integrated analysis identified core signal pathways and hypoxic characteristics of human glioblastoma. J Cell Mol Med. 23:6228–6237. 2019.PubMed/NCBI View Article : Google Scholar

33 

Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D and Rocha S: Mechanism of hypoxia-induced NF-kappaB. Mol Cell Biol. 30:4901–4921. 2010.PubMed/NCBI View Article : Google Scholar

34 

Wang P, Zhao L, Gong S, Xiong S, Wang J, Zou D, Pan J, Deng Y, Yan Q, Wu N and Liao B: HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia. Cell Death Dis. 12(312)2021.PubMed/NCBI View Article : Google Scholar

35 

Luo Z, Tian M, Yang G, Tan Q, Chen Y, Li G, Zhang Q, Li Y, Wan P and Wu J: Hypoxia signaling in human health and diseases: Implications and prospects for therapeutics. Signal Transduc Target Ther. 7(218)2022.PubMed/NCBI View Article : Google Scholar

36 

Unwith S, Zhao H, Hennah L and Ma D: The potential role of HIF on tumour progression and dissemination. Int J Cancer. 136:2491–2503. 2015.PubMed/NCBI View Article : Google Scholar

37 

Lv X, Li J, Zhang C, Hu T, Li S, He S, Yan H, Tan Y, Lei M, Wen M and Zuo J: The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes Dis. 4:19–24. 2016.PubMed/NCBI View Article : Google Scholar

38 

Awuah WA, Toufik A-R, Yarlagadda R, Mikhailova T, Mehta A, Huang H, Kundu M, Lopes L, Benson S, Mykola L, et al: Exploring the role of Nrf2 signaling in glioblastoma multiforme. Discov Oncol. 13(94)2022.PubMed/NCBI View Article : Google Scholar

39 

Adinolfi S, Patinen T, Jawahar Deen A, Pitkänen S, Härkönen J, Kansanen E, Küblbeck J and Levonen AL: The KEAP1-NRF2 pathway: Targets for therapy and role in cancer. Redox Biol. 63(102726)2023.PubMed/NCBI View Article : Google Scholar

40 

Zhang J, Xu HX, Zhu JQ, Dou YX, Xian YF and Lin ZX: Natural Nrf2 inhibitors: A review of their potential for cancer treatment. Int J Biol Sci. 19:3029–3041. 2023.PubMed/NCBI View Article : Google Scholar

41 

Harifi-Mood MS, Alemzadeh E, Barati D, Dehghani AH, Siroosi FZ, Aschner M, Samini F, Samarghandian S and Farkhondeh T: The role of Nrf2 in glioma: Therapeutic targeting strategies. Curr Cancer Drug Targets: February 14, 2025 (Epub ahead of print).

42 

Syu JP, Chi JT and Kung HN: Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia. Oncotarget. 7:14659–14672. 2016.PubMed/NCBI View Article : Google Scholar

43 

He T, Zhou F, Su A, Zhang Y, Xing Z, Mi L, Li Z and Wu W: Brusatol: A potential sensitizing agent for cancer therapy from Brucea javanica. Biomed Pharmacother. 158(114134)2023.PubMed/NCBI View Article : Google Scholar

44 

Kolamunne RT, Dias IHK, Vernallis AB, Grant MM and Griffiths HR: Nrf2 activation supports cell survival during hypoxia and hypoxia/reoxygenation in cardiomyoblasts; the roles of reactive oxygen and nitrogen species. Redox Biol. 1:418–426. 2013.PubMed/NCBI View Article : Google Scholar

45 

Lu Y, Wang B, Shi Q, Wang X, Wang D and Zhu L: Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells. Sci Rep. 6(39123)2016.PubMed/NCBI View Article : Google Scholar

46 

Shostak K and Chariot A: EGFR and NF-κB: Partners in cancer. Trends Mol Med. 21:385–393. 2015.PubMed/NCBI View Article : Google Scholar

47 

Zhang M, Zhang YY, Chen Y, Wang J, Wang Q and Lu H: TGF-β signaling and resistance to cancer therapy. Front Cell Dev Biol. 9(786728)2021.PubMed/NCBI View Article : Google Scholar

48 

Uribe ML, Marrocco I and Yarden Y: EGFR in cancer: Signaling mechanisms, drugs, and acquired resistance. Cancers (Basel). 13(2748)2021.PubMed/NCBI View Article : Google Scholar

49 

Gong L, Yin Y, Chen C, Wan Q, Xia D, Wang M, Pu Z, Zhang B and Zou J: Characterization of EGFR-reprogrammable temozolomide-resistant cells in a model of glioblastoma. Cell Death Discov. 8(438)2022.PubMed/NCBI View Article : Google Scholar

50 

Lee SLO, Ryu H, Son AR, Seo B, Kim J, Jung SY, Song JY, Hwang SG and Ahn J: TGF-β and hypoxia/reoxygenation promote radioresistance of A549 lung cancer cells through activation of Nrf2 and EGFR. Oxid Med Cell Longev. 2016(6823471)2016.PubMed/NCBI View Article : Google Scholar

51 

Lim SW, Chen WC, Ko HJ, Su YF, Wu CH, Huang FL, Li CF and Tsai CY: 6-Gingerol induced apoptosis and cell cycle arrest in glioma cells via MnSOD and ERK phosphorylation modulation. Biomol Ther (Seoul). 33:129–142. 2025.PubMed/NCBI View Article : Google Scholar

52 

Lyons A, Coleman M, Riis S, Favre C, O'Flanagan CH, Zhdanov AV, Papkovsky DB, Hursting SD and O'Connor R: Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells. J Biol Chem. 292:16983–16998. 2017.PubMed/NCBI View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Tripatara P, Onkoksoong T, Prasopporn S, Sathornsumetee S, Jirawatnotai S and Panich U: Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia. Biomed Rep 25: 129, 2026.
APA
Tripatara, P., Onkoksoong, T., Prasopporn, S., Sathornsumetee, S., Jirawatnotai, S., & Panich, U. (2026). Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia. Biomedical Reports, 25, 129. https://doi.org/10.3892/br.2026.2202
MLA
Tripatara, P., Onkoksoong, T., Prasopporn, S., Sathornsumetee, S., Jirawatnotai, S., Panich, U."Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia". Biomedical Reports 25.5 (2026): 129.
Chicago
Tripatara, P., Onkoksoong, T., Prasopporn, S., Sathornsumetee, S., Jirawatnotai, S., Panich, U."Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia". Biomedical Reports 25, no. 5 (2026): 129. https://doi.org/10.3892/br.2026.2202
Copy and paste a formatted citation
x
Spandidos Publications style
Tripatara P, Onkoksoong T, Prasopporn S, Sathornsumetee S, Jirawatnotai S and Panich U: Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia. Biomed Rep 25: 129, 2026.
APA
Tripatara, P., Onkoksoong, T., Prasopporn, S., Sathornsumetee, S., Jirawatnotai, S., & Panich, U. (2026). Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia. Biomedical Reports, 25, 129. https://doi.org/10.3892/br.2026.2202
MLA
Tripatara, P., Onkoksoong, T., Prasopporn, S., Sathornsumetee, S., Jirawatnotai, S., Panich, U."Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia". Biomedical Reports 25.5 (2026): 129.
Chicago
Tripatara, P., Onkoksoong, T., Prasopporn, S., Sathornsumetee, S., Jirawatnotai, S., Panich, U."Nrf2 and PGC‑1&alpha; signaling in temozolomide resistance in glioblastoma under hypoxia". Biomedical Reports 25, no. 5 (2026): 129. https://doi.org/10.3892/br.2026.2202
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team